Grant: Research Tools and Instruments

We request an urgently needed ion mobility mass spectrometry (IM/MS) instrument for hydrogen/deuterium exchange (HDX) measurements that will elucidate the role of proteins in health and disease. HDX techniques are essential for probing protein dynamics. Flexible segments undergo rapid HDX, while deuteration in folded regions is slow. This information is complementary to data from X-ray crystallography, cryo-electron microscopy, and NMR spectroscopy. HDX techniques have the unique advantage that they can report on functionally important protein dynamics in situ , while proteins perform their biological tasks. The size range accessible by HDX extends all the way to the largest protein complexes. The applicants represent a team of internationally renowned researchers that has already established a productive network of interdisciplinary collaborations. Konermanns laboratory (where the new instrument will be installed) will be the central hub for the HDX activities associated with the research of all six applicants. As recipient of numerous HDX and MS-related awards, Konermann is uniquely qualified to spearhead these activities. The proposed equipment (a Waters Synapt G2S) is a state-of-the-art IM/MS instrument. It has been offered by the manufacturer for this RTI competition at a deeply discounted price. The G2S is an emergency replacement for an obsolete old instrument that is on the verge of permanent breakdown. The greatly enhanced sensitivity and peak capacity of the new instrument will allow us to enter previously inaccessible realms, such as a detailed characterization of key transmembrane protein segments. The research enabled by the IM/MS instrument will break new ground by providing unprecedented insights into the motions of protein systems in their working state. Studies on molecular motors will reveal intricate details related to power transmission, friction, and energy coupling. We will also interrogate how proteins involved in Parkinsons disease and cancer interact with their biological binding partners. HDX experiments on proteins from cold- and heat-adapted organisms will uncover fundamental aspects of enzyme function. The benefits associated with this proposal are enormous. The new instrument is essential for our HQP training and recruitment activities. It will provide trainees with essential skills, keeping in mind that mass spectrometry is the most widely used analytical technique in industry, academia, government agencies, and in clinical laboratories. Research enabled by this proposal will provide a greatly improved understanding of protein-based molecular machines, paving the way towards technological and therapeutic opportunities. We will also uncover important aspects related to neurodegenerative diseases, bacterial infections, and cancer. In summary, this RTI grant promises an exceptional return on investment.